The MACPF/CDC family of pore-forming toxins

Summary Pore-forming toxins (PFTs) are commonly associated with bacterial pathogenesis. In eukaryotes, how- ever, PFTs operate in the immune system or are de- ployed for attacking prey (e.g. venoms). This review focuses upon two families of globular protein PFTs: the cholesterol-dependent cytolysins (CDCs) and the membrane attack complex/perforin superfamily (MACPF). CDCs are produced by Gram-positive bac- teria and lyse or permeabilize host cells or intracellu- lar organelles during infection. In eukaryotes, MACPF proteins have both lytic and non-lytic roles and func- tion in immunity, invasion and development. The structure and molecular mechanism of several CDCs are relatively well characterized. Pore formation involves oligomerization and assembly of soluble monomers into a ring-shaped pre-pore which under- goes conformational change to insert into mem- branes, forming a large amphipathic transmembrane b-barrel. In contrast, the structure and mechanism of MACPF proteins has remained obscure. Recent crys- tallographic studies now reveal that although MACPF and CDCs are extremely divergent at the sequence level, they share a common fold. Together with bio- chemical studies, these structural data suggest that lytic MACPF proteins use a CDC-like mechanism of membrane disruption, and will help understand the roles these proteins play in immunity and development.